PROJECT SUMMARY The complexity and multifactorial nature of Alzheimer's disease (AD) poses unique challenges for mechanistic studies and developing therapies. Efforts to target AD-related pathways have shown promise in animal studies, only to fail during human trials. Thus, there remains a pressing need to identify novel mechanisms and therapeutic targets for treating or preventing AD. One of the earliest sites of AD pathology is the hippocampus, a brain structure critical for the learning and memory processes that falter early in AD. Decades of research have yielded insight into the genetics and cellular pathologies of the disease, but it is unclear how these pathologies disrupt hippocampal memory processes. The main genetic risk factor for AD is apolipoprotein (apo) E4, which lowers the age of onset of AD in a gene dose?dependent manner. In most clinical studies, apoE4 carriers account for 60?75% of all AD cases, highlighting the importance of apoE4 in AD pathogenesis. Although many hypotheses have been proposed, the cellular and network mechanisms underlying the pathophysiological actions of apoE4 are still unclear. This proposal builds on novel findings from our recent studies of mouse models. First, expression of apoE4 in knock-in (KI) mice causes age-dependent impairment of GABAergic interneurons in the hilus of the hippocampus, which correlates with the severity of learning and memory deficits. Second, deleting the apoE4 gene specifically in GABAergic interneurons prevents hilar interneuron loss and learning and memory deficits in LoxP-floxed apoE4-KI (apoE4-fKI) mice. Third, in vivo local field potential (LFP) recordings throughout the hippocampal circuit shows that compared to aged apoE3-KI mice, aged apoE4-KI mice have fewer sharp wave ripple (SWR) events?hippocampal network events critical for memory replay and consolidation?and have significantly reduced slow gamma activity during SWRs, which coordinates SWRs. Fourth, elimination of apoE4 in GABAergic interneurons rescues SWR-associated slow gamma activity but not SWR abundance in apoE4-fKI mice, suggesting that the disruption of interneuron-enabled slow gamma activity during SWRs is a critical mechanism of apoE4-mediated learning and memory impairments. This proposal aims (1) to determine the relative contribution of inhibitory interneuron subtypes to apoE4 disruption of hippocampal network activity underlying memory replay and (2) to determine whether apoE4 disruption of hippocampal network activity underlying memory replay depends on A?, tau, or both. The outcomes of the proposed studies will shed light on the pathogenesis of late-onset AD and could provide new targets for developing drugs treating or preventing AD.